TERATOLOGY 45~345-351 (1992)
Further Evidence That Arthrogryposis Multiplex Congenita in the Human Sometimes Is Caused by an Intrauterine Vascular Accident WENDY L. ROBERTSON, LISA P. GLINSKI, SUSAN J. KIRKPATRICK, RICHARD M. PAUL1 Departments of Medical Genetics (W.L.R., L.P.G., S.JX., R.M.P.) and Pediatrics (R.M.P.), University of Wisconsin-Madison, Madison, Wisconsin 53705 AND
ABSTRACT
A 7%-year-old girl with arthrogryposis multiplex congenita of the amyoplasia type in association with intestinal atresias, gastroschisis, Mobius anomaly, and hypoplasia of the pectoral, biceps, and deltoid muscles is described. Several combinations of these birth defects have been previously described. There is considerable evidence that gastroschisis, intestinal atresia, Poland sequence, and Mobius anomaly each has a vascular pathogenesis. Based on the associations seen in this child and past reports of more limited, similar cooccurrences, we suggest that arthrogryposis multiplex congenita may sometimes be caused by an intrauterine vascular catastrophe.
The combination of arthrogryposis multiplex congenita (AMC), intestinal atresias, gastroschisis, Poland sequence, and Mobius anomaly has not been reported previously; however, several dyad and triad associations of these defects have been described (Collins et al., '86; Hall et al., '83; Hanissian et al., '70; Henderson, '39; Hoyme et al., '81; Ilyina, '88; Maino and Scharre, '89; Reid et al., '86; Richards, '53; Sprofkin and Hillman, '56; Sudarshan and Goldie, '85). Evidence suggests that individually intestinal atresia (Louw and Barnard, '55), gastroschisis (Hoyme et al., '81), the Poland sequence (Bouvet et al., '78; Merlob et al., '89), and some cases of Mobius anomaly (Govaert et al., '89; Kuhn et al., '90) may develop secondary to vascular disruption. We describe a 7 and Yz-year-old girl with AMC of the amyoplasia type associated with intestinal atresias, gastroschisis, bilateral hypoplasia of the pectoral, biceps, and deltoid muscles, and Mobius anomaly. Their cooccurrence suggests a common pathogenesis. CASE DESCRIlTION
The patient was born by vaginal delivery with frank breech presentation at term to young, healthy parents (mother G3PlTAbl) with normal family histories. Pregnancy was notable for markedly decreased intrauterine movement, but was uncomplicated 0 1992 WILEY-LISS, INC.
by any unusual exposures to illnesses except for pneumonia in the last month of pregnancy which was treated with penicillin, and mild late onset gestational diabetes controlled by diet. Oligohydramnios was noted at the time of spontaneous rupture of membranes. Birthweight was 2715 g, birthlength unrecorded, and birth head circumference 33.5 cm. Apgar scores were 0 and 6 at 1and 5 mins; asphyxia was attributed to breech extraction and vigorous resuscitation was quickly successful. There was a three vessel cord; no placental evaluation was completed. Multiple congenital anomalies were recognized at birth: gastrochisis, limb and chest wall hypoplasia, abnormalities of facial expression, and multiple contractures. Chromosome evaluation revealed a normal female karyotype: 46,XX. Shortly after birth, intestinal abnormalities including atresia of the most distal ileum, cecum, and ascending colon and mesenteric nonattachment were discovered. The last resulted in torsion around the superior mesenteric artery and secondary gan-
Received August 16, 1991; accepted November 12, 1991. Address reprint requests to Richard M. Pauli, M.D., Ph.D., Clinical Genetics Center, Room 353, 1500 Highland Avenue, Madison. WI 53705.
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Fig. 1. Age 7Yz years. Note bilateral decreased mass of shoulder girdle, pectoral, and proximal arm musculature.
grenous destruction of virtually all of the remaining ileum. Resection resulted in short gut syndrome, successfully treated with long-term central hyperalimentation. Eventually most of the symptoms associated with short gut syndrome resolved. A right, periumbilical gastroschisis, 4 cm in diameter resulted in extrusion of the stomach and all of the small bowel. The gastroschisis was repaired a t the time of intestinal resection. No contralateral abdominal wall defect (Reid et al., '86) was present. Bilateral decreased size and weakness of the upper limbs, shoulder girdle, and chest wall were noted in the newborn period. Electromyography in the arms failed to demonstrate any specific myopathic or neuropathic process. Examination at age 7% years showed the following: the biceps muscles were markedly decreased in mass bilaterally, as were the deltoids, while the triceps showed less severe hypoplasia; shoulder girdle musculature was hypoplastic with the left side slightly more severely affected than the right; pectoral muscles and the anterior axillary folds were also asymmetrically hypoplastic with the left side slightly less severely affected (Fig. 1).
Abnormalities of facial expression and a glabellar hemangioma were recognized a t birth. By clinical examination and electromyography with nerve conduction studies severe paresis of both the upper and lower distribution of the left VIIth cranial nerve could be demonstrated, including ipsilateral virtual absence of facial expression and marked limitation of voluntary movement of periorbital and perioral muscles. When examined a t 7% years of age these findings were still present: there was obvious facial asymmetry associated with markedly decreased resting tone of the muscles on the left (muscle mass seemed symmetric) without involvement of the muscles of mastication (Fig. 2A). In addition, examination showed absence of lateral rectus function bilaterally (Fig. 2B,C) indicative of bilateral VIth nerve paresis (left greater than right) as well as possible partial left IIIrd paresis suggested by poor inward gaze of the left eye (Fig. 2C). Tongue was normal in bulk, movement, and symmetry, and palatal elevation and gag reflex were normal. There were no facial anomalies other than those explicable on the basis of cranial nerve dysfunction. Limitation of arm and hand movement was recognized a t birth, including elbows fixed in extension, wrists fixed in flexion, ulnar deviation of the hands, and flexional camptodactyly of the fingers. Examination at age 7% years showed anterior sloping of the shoulders, prominent superficial venous patterning over the anterior trunk (Fig. 11, moderate limitation of shoulder mobility including elevation only to neutral bilaterally, and limited elbow flexion (5"-90" on the right and 10"-110"on the left) with limited supination on the left. Wrists were limited in dorsiflexion (90"-0" on the right and 100"-10" on the left). Hands showed camptodactylic contractures (Fig. 3) as follows. On the right the fifth finger had moderate limitation of metacarpal phalangeal joint (MCP) movement, marked limitation of proximal interphalangeal joint (PIP) movement, and flexion contracture of the distal interphalangeal joint (DIP); the fourth finger had an MCP which was fixed in extension, a PIP which showed 30" of flexion only, and a DIP which was also fixed in extension; the third finger had near normal MCP movement, severe f lexional camptodactyly with a tissue web of the PIP, and normal DIP movement; the second finger
VASCULAR ORIGIN OF ARTHROGRYPOSIS
347
Fig. 2. Age 7Yz years (A) Weakness of facial muscles on left with asymmetric nasolabial folds is evident. (B,C) Patient attempts forced lateral gaze to the left and right, respectively, showing bilateral VIth nerve paralysis and probable left IIIrd nerve paresis.
Fig. 3. Age 7% years. Arthrogrypotic hand abnormalities.
had a normal MCP, a fixed PIP, and a virtually normal DIP; the thumb was adducted and stiff but showed reasonably good opposition. On the left the fifth finger had good MCP mobility, mild limitation of PIP movement, and a DIP held completely flexed and immobile; the fourth finger had the MCP
and PIP fixed in extension, and moderate limitation of DIP mobility; the third finger had near normal MCP movement, a PIP fixed in extension, and normal DIP movement; the second finger was normal except that the PIP was fixed in extension; the thumb was normal.
348
W.L.ROBERTSON ET AL. ~~
Intestinal Atresia
AMC
Gestroschisis
Mobius Anomaly
Poland Sequence
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Fig. 4. Summary of reports of associations among arthrogryposis multiplex congenita (AMC), intestinal atresia, gastroschisis, Mobius anomaly, and Poland sequence (including isolated pectoral hypoplasia). Nine of the 26 possible combinations have now been described.
The large filled circles indicate three or more reported cases, small filled circles are used where there have been only one or two reported instances, and open circles are for associations which have not yet been described.
Legs were uninvolved except for mild bilateral calcaneovalgus deformity of both feet in infancy. By age 7?f!z years legs and feet were normal except that the left foot was 1 cm longer than the right and that the toes were irregular in placement with mild overlap bilaterally. Other findings at 7% years of age included bilateral dimples over the acromion processes, mild lumbar lordosis, and diffuse hirsutism of the lower lumbar and sacral
region. Height was 104.4 cm (< 3rd %ile) and weight 17.2 kg (3rd %ile). She was mildly brachycephalic and had a head circumference of 49.3 cm (10th %ile). Intellectual development has been normal. Normal evaluations, in addition to those already mentioned, included echocardiography, computerized tomography of the calvarium, brainstem auditory evoked response testing, and electroencephalograPhY*
VASCULAR ORIGIN OF ARTHROGRYPOSIS DISCUSSION
Each of the five major characteristics present in this patient is typical in comparison to previous descriptions of their occurrence in isolation with the exception of the Poland sequence-like chest wall hypoplasia. There is nothing distinctive about the nonduodenal intestinal polyatresias with associated abnormalities of the mesentery when compared with instances in which this defect is unassociated with additional birth defects (Louw and Barnard, '55). Typical right sided gastroschisis not involving the umbilicus (Hoyme et al., '81) was present. As seen here, gastroschisis is most often right sided, probably because of asymmetric embryological vascular development in the abdominal wall (Hoyme et al., ,811. Mobius anomaly most often includes abnormality of lateral gaze (VIth nerve paresis) frequently with additional cranial pareses, most often of the VIIth cranial nerve (Van Allen and Blodi, '60) as was seen in this patient. The descriptive and nonspecific diagnosis of AMC was apparent a t birth. Subsequent assessment showed a constellation of contractures and posture consistent with the more specific diagnosis of amyoplasia (Hall et al., '83). Unilateral or asymmetric hypoplasia of the pectoral muscles may represent one end of a continuous spectrum of Poland sequence (Sujansky et al., '77; McGillivray and Lowry, '77). The complete Poland sequence consists of unilateral absence of the sternocostal head of the pectoralis major in association with syndactyly or symbrachydactyly (Poland, 1841). This patient is atypical even for Poland sequence variant because she has nearly symmetric bilateral involvement and more generalized muscular hypoplasia. However, all muscles which appear to be principally involved are supplied by the subclavian, axillary, and brachial arteries. Evidence suggests that each of the abnormalities present in this child, when found in isolation, has a vascular disruptive basis. Nonduodenal intestinal atresias and abnormalities of the mesentery have a well documented and experimentally demonstrated basis of vascular disruption. Louw and Barnard ('55) provided two kinds of evidence: autopsy findings from three patients with intestinal atresias showed associated absence of the inferior mesenteric arteries; ligation of the mesenteric arteries in fetal
349
puppies predictably resulted in intestinal atresias and abnormalities of the mesentery. Hoyme et al. ('81) have suggested that intrauterine interruption of the omphalomesenteric artery can lead to gastroschisis, an argument based both upon the recognized vascular pathogenesis of associated defects and on embryological development of the vasculature of the abdominal wall. The proximal portion of the right omphalomesenteric artery gives rise to the superior mesenteric artery. Their developmental interrelatedness has led to the hypothesis that abnormalities of the proximal portion of the right omphalomesenteric artery may lead to coexisting intestinal atresias in association with gastroschisis (Hoyme et al., '81). There is also evidence to suggest a vascular pathogenesis for the Poland sequence. Rheographic studies of the vasculature of eight patients showed decreased blood flow velocity on the affected side (Bouvet et al., '78) and Doppler scanning showed decreased diameter of the subclavian artery on the affected side (Merlob et al., '89). Bavinck and Weaver ('86) presented a coherent model of subclavian artery supply disruption as the basis for Poland sequence. Evidence in support of a vascular disruptive pathogenesis for Mobius anomaly is not so compelling. Indeed, there is considerable debate over the site of the primary lesion-whether it is the cranial nerve nuclei within the brainstem, the cranial nerves outside of the brainstem, or the extraocular muscles which are primarily affected (Pitner et al., '65).Several case reports suggest a primary lesion within the cranial nerve nuclei (Henderson, '39; Thakkar et al., '77). More recently Govaert et al. ('89) and Kuhn et al. ('90) showed by neuroimaging of patients with Mobius anomaly that there were cranial nerve nuclei abnormalities including calcifications. Such calcification may be most consistent with a prenatal ischemic event (Govaert et al., '89). A model for prenatal disruption of the vertebral arteries and/or basilar artery resulting in Mobius anomaly has been suggested (Bavinck and Weaver, '86). In addition, Lipson et al. ('89) found some evidence for vascular causes of Mobius anomaly in 15 human cases. There is less direct support of a vascular pathogenesis for AMC. Horoupian and Yoon ('80) described three instances of AMC in which anterior horn cell loss and ferrugination of some remaining neurons was found, indicat-
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W.L. ROBERTSON ET AL
ing that neuronal destruction was most likely due to an ischemic event. Reid et a1 ('86) suggested that fetal and/or maternal vascular compromise during a critical period in the development of anterior horn cells may result in AMC, conceivably secondary to disruption of anterior spinal arteries (Lazorthes et al., '71). Associations of various combinations of the abnormalities seen in this child have been described (Fig. 4). Each of these coassociations independently supports the idea that all of the associated processes have a single pathogenetic basis-that is, vascular disruption. Reported dyad associations include gastroschisis and intestinal atresias (Hoyme et al., %l), Mobius anomaly and Poland sequence (Maino and Scharre, '89; Richards, '53), AMC and Mobius anomaly (Goldie, '85;Hanissian et al., '70; Sudarshan and Henderson, '391, AMC and Poland sequence (Sprofkin and Hillman, '561, AMC and intestinal atresia (Ilyina, '88; Reid et al., '86; Collins et al., '86), and AMC and gastroschisis (Reid et al., '86; Hall, Reed and Driscoll, '83). Two instances of triad combinations were found: AMC, intestinal atresias, and gastroschisis (Reid et al., '86>, and AMC, Mobius anomaly, and pectoral hypoplasia (Sprofkin and Hillman, '56). For the five characteristics seen in the patient reported here, by binomial expansion ( n= 5 , r 2 2 ) 26 such associations would be expected, of which, including this report, a t least eight have thus far been recognized. It is unlikely that any of these dyad and triad associations arose coincidentally. It is even less likely that the combination of all five abnormalities seen in this child would arise by chance. Rather, cooccurrence of arthrogryposis with four other apparently vascular-based abnormalities further supports the notion that arthrogryposis may have a vascular disruptive basis. In addition to those already discussed, other disorders for which a primary vascular disruptive event has been postulated include aplasia cutis congenita (Jaeggli et al., 'go), hemifacial microsomia (Poswillo, '731, porencephaly and other structural brain anomalies (Schinzel et al., '79), septooptic dysplasia (Mosier et al., '78), Klippel-Feil anomaly (Brill et al., '87), other vertebral anomalies (Bavinck and Weaver, '861, Sprengel deformity (Bavinck and Weaver, '86), terminal transverse limb defects (Hoyme et al., '82), radial ray anomalies
(Van Allen et al., '821, sirenomelia (Stevenson et al., '86), clubfoot (Hootnick et al., '82), twin-twin artery-artery disruptions (Benirschke and Harper, '771, and early amnionflimb-body wall disruptions (Luebke et al., '90). For 18 such vascularassociated birth defects (those listed above plus those present in the patient described-a conservative set of those disorders in which there is a t least some evidence for a vascular pathogenesis) a total of 310,745 different cooccurrences would be anticipated ( n= 18, 7-22), leaving about 310,700 still to be clinically identified! In the patient reported here, a vascular disruptive pathogenesis for all five characteristics would require disruption of the superior mesenteric artery, omphalomesenteric artery, vertebral and/or basilar arteries, subclavian arteries, and anterior spinal arteries. Based on the embryological development of these vessels we suggest that either a simultaneous disruption or a cluster of disruptive events occurred at around 6 to 8 weeks postconception (Hamilton et al., '72).What primary event resulted in such diffuse vascular or hypoxic effects is undetermined. LITERATURE CITED Bavinck, J.N.B., and D.D. Weaver (1986) Subclavian artery supply disruption sequence: Hypothesis of a vascular etiologyfor Poland, Klippel-Feil,and Mobius anomalies. Am. J. Med. Genet., 23:903-918. Benirschke, K., and V.D.R. Harper (1977) The acardiac anomaly. Teratology, 15:311-316. Bouvet, J.-P., D. Leveque, F. Bernetieres, and J . J . Gros (1978) Vascular origin of Poland syndrome? A comparative rheographic study of the vascularisation of the arms in eight patients. Eur. J. Pediatr., 128:1726. Brill, C.B., R.G. Peyster, M.S. Keller, and L. Galtman (1987) Isolation of the right subclavian artery with subclavian steal in a child with Klippel-Feil anomaly: An example of the subclavian artery supply disruption sequence. Am. J. Med. Genet., 26:933-940. Collins, D.L., K. Kimura, A. Morgan, D.G. Johnson, C. Leonard, and M.C. Jones (1986) Multiple intestinal atresia and amyoplasia congenita in four unrelated infants: A new association.J. Pediatr. Surg., 21 :331333. Govaert, P., P. Vanhaesebrouck, C. De F'raeter, U. Frankel, and J . Leroy (1989) Moebius sequence and prenatal brainstem ischemia. Pediatrics, 84570-573. Hall, J.G., S.D. Reed, and E.P. Driscoll (1983) Part I. Amyoplasia: A common, sporadic condition with congenital contractures. Am. J. Med. Genet., 15:571-590. Hamilton, W.J., J.D. Boyd, and H.W. Mossman (1972) Human Embryology,4th ed. Williams & Wilkins, Baltimore. Hanissian, A.S., F. Fuste, W.T. Hayes, and J.M. Duncan (1970) Mobius syndrome in twins. Am. J . Dis. Child., 120:472-475.
VASCULAR ORIGIN OF ARTHROGRYPOSIS Henderson, J.L. (1939) The congenital facial diplegia features, pathology and etiology. Hootnick, D.R., E.M. Levinsohn, R.J. Crider, and D.S. Packard (1982) Congenital arterial malformations associated with clubfoot A report of two cases. Clin. Orthop., 167: 160-163. Horoupian D.S., and J.J. Yoon (1988) Neuropathic arthrogryposis multiplex congenita and intrauterine ischemia of anterior horn cells: a hypothesis. Clin. Neuropathol., 7:285-293. Hoyme, H.E., M.C. Higginbottom, and K.L. Jones (1981) The vascular pathogenesis of gastroschisis: Intrauterine interruption of the omphalomesentericartery. J. Pediatr., 98:228-231. Hoyme, H.E., K.L. Jones, M.I. Van Allen, B.S. Saunders, and K. Benirschke (1982) Vascular pathogenesis of transverse limb reduction defects. J. Pediatr., 101:839-843. Ilyina, H.G. (1988) Intestinal atresia and arthrogryposis. Am. J. Med. Genet., 29:673-674. Jaeggi, E., C. Kind, and R. Morger (1990) Congenital scalp and skull defects with terminal transverse limb anomalies (Adams-Oliver syndrome): Report of three additional cases. Eur. J. Pediatr., 149~565-566. Kuhn, M.J., H.B. Clark, A. Morales, and P.C. Shekar (1990) Group 111 Mobius syndrome: CT and MR findings. Am. J. Neuroradiol., 11:903-904. Lazorthes, G., A. Gouaze, J.O. Zadeh, J.J. Santini, Y. Lazorthes, and P. Burdin (1971) Arterial vascularization of the spinal cord Recent studies of the anastomotic substitution pathways. J . Neurosurg., 35:253262. Lipson, A.H., W.S. Webster, P.D.C. Brown-Woodman, and R.A. Osborn (1989) Moebius syndrome: Animal model-human correlations and evidence for a brainstem vascular etiology. Teratology, 40:339-350. Louw, J.H., and C.N. Barnard (1955) Congenital intestinal atresia: Observations on its origin. Lancet, 2: 1065-1067. Luebke, H.J., C.A. Reiser, and R.M. Pauli (1990) Fetal disruptions: Assessment of frequency, heterogeneity, and embryologic mechanisms in a population referred to a community-based stillbirth assessment program. Am. J. Med. Genet., 36:56-72. Maino, D.M., and J.E. Scharre (1989) Poland-Mobius syndrome: A case report. Opt. Vision Sci., 66:621-625. McGillivray, B.C., and R.B. Lowry (1977) Poland syndrome in British Columbia: Incidence and reproductive experience of affected persons. Am. J . Med. Genet., 1:65-74. Merlob, P., A. Schonfeld, Y. Ovadia, and S.H. Reisner
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(1989) Real-time echo-doppler duplex scanner in the evaluation of patients with Poland sequence. Eur. J . Obstet. Gynecol. Reprod. Biol., 32:103-108. Mosier, M.A., M.F. Lieberman, W.R. Green, and D.L. Knox (1978) Hypoplasia of the optic nerve. Arch. Ophthalmol., 96~1437-1442. Pitner, S.E., J.E. Edwards, and W.F. McCormick (1965) Observations on the pathology of Moebius syndrome. J . Neurol. Neurosurg. Psychiat., 28:362-374. Poland, A. (1841) Deficiency of the pectoral muscles. Guy Hosp. Report, 6:191-192. Poswillo, D. (1973) The pathogenesis of the first and second branchial arch syndrome. Oral Surg. Oral Med. Oral Pathol., 35:302-328. Reid, C.O.M.V., J.G. Hall, C. Anderson, M. Bocian, J . Carey, T. Costa, C. Curry, F. Greenberg, E.W. Horton, M. Jones, C. Lafer, E. Larson, M. Lubinsky, B. McGillivray, M. Pembry, J. Popkin, M. Seller, V. Siebert, and A. Verhagen (1986) Association of amyoplasia with gastroschisis, bowel atresia, and defects of the muscular layer of the trunk. Am. J . Med. Genet., 24:701-710. Richards, R.N. (1953) The Mobius syndrome. J . Bone Joint Surg. (A), 35:437-444. Schinzel, A.A.G.L., D.W. Smith, and J.R. Miller (1979) Monozygotic twinning and structural defects. J . Pediatr., 95:921-930. Sprofkin, B.E., and J.W. Hillman (1956) Moebius's syndrome-congenital oculofacial paralysis. Neurology, 6:50-54. Stevenson, R.E., K.L. Jones, M.C. Phelan, M.C. Jones, M. Barr, C. Clericuzio, R.A. Harley, and K. Benirschke (1986) Vascular steal: The pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics, 78:451-457. Sudarshan, A. and W.D. Goldie (1985) The spectrum of congenital facial diplegia (Moebius syndrome). Pediatr. Neurol., 1:180-184. Sujansky, E., V.M. Riccardi, and A.L. Matthew (1977) The familial occurrence of Poland syndrome. Birth Defects, I3(3A):117-121. Thakkar, N., W. ONeill, J . Duvally, C. Liu, and M. Ambler (1977) Mobius syndrome due to brain stem tegmental necrosis. Arch. Neurol., 34:124-126. Van Allen, M.I., H.E. Hoyme, and K.L. Jones (1982) Vascular pathogenesis of limb defects. I. Radial artery anatomy in radial aplasia. J . Pediatr., 101:832-838. Van Allen, M.W., and F.C. Blodi (1960) Neurologic aspects of the Mobius syndrome: A case study with electromyography of the extraocular and facial muscles. Neurology, 10:249-259.
Further Evidence That Arthrogryposis Multiplex Congenita in the Human Sometimes Is Caused by an Intrauterine Vascular Accident WENDY L. ROBERTSON, LISA P. GLINSKI, SUSAN J. KIRKPATRICK, RICHARD M. PAUL1 Departments of Medical Genetics (W.L.R., L.P.G., S.JX., R.M.P.) and Pediatrics (R.M.P.), University of Wisconsin-Madison, Madison, Wisconsin 53705 AND
ABSTRACT
A 7%-year-old girl with arthrogryposis multiplex congenita of the amyoplasia type in association with intestinal atresias, gastroschisis, Mobius anomaly, and hypoplasia of the pectoral, biceps, and deltoid muscles is described. Several combinations of these birth defects have been previously described. There is considerable evidence that gastroschisis, intestinal atresia, Poland sequence, and Mobius anomaly each has a vascular pathogenesis. Based on the associations seen in this child and past reports of more limited, similar cooccurrences, we suggest that arthrogryposis multiplex congenita may sometimes be caused by an intrauterine vascular catastrophe.
The combination of arthrogryposis multiplex congenita (AMC), intestinal atresias, gastroschisis, Poland sequence, and Mobius anomaly has not been reported previously; however, several dyad and triad associations of these defects have been described (Collins et al., '86; Hall et al., '83; Hanissian et al., '70; Henderson, '39; Hoyme et al., '81; Ilyina, '88; Maino and Scharre, '89; Reid et al., '86; Richards, '53; Sprofkin and Hillman, '56; Sudarshan and Goldie, '85). Evidence suggests that individually intestinal atresia (Louw and Barnard, '55), gastroschisis (Hoyme et al., '81), the Poland sequence (Bouvet et al., '78; Merlob et al., '89), and some cases of Mobius anomaly (Govaert et al., '89; Kuhn et al., '90) may develop secondary to vascular disruption. We describe a 7 and Yz-year-old girl with AMC of the amyoplasia type associated with intestinal atresias, gastroschisis, bilateral hypoplasia of the pectoral, biceps, and deltoid muscles, and Mobius anomaly. Their cooccurrence suggests a common pathogenesis. CASE DESCRIlTION
The patient was born by vaginal delivery with frank breech presentation at term to young, healthy parents (mother G3PlTAbl) with normal family histories. Pregnancy was notable for markedly decreased intrauterine movement, but was uncomplicated 0 1992 WILEY-LISS, INC.
by any unusual exposures to illnesses except for pneumonia in the last month of pregnancy which was treated with penicillin, and mild late onset gestational diabetes controlled by diet. Oligohydramnios was noted at the time of spontaneous rupture of membranes. Birthweight was 2715 g, birthlength unrecorded, and birth head circumference 33.5 cm. Apgar scores were 0 and 6 at 1and 5 mins; asphyxia was attributed to breech extraction and vigorous resuscitation was quickly successful. There was a three vessel cord; no placental evaluation was completed. Multiple congenital anomalies were recognized at birth: gastrochisis, limb and chest wall hypoplasia, abnormalities of facial expression, and multiple contractures. Chromosome evaluation revealed a normal female karyotype: 46,XX. Shortly after birth, intestinal abnormalities including atresia of the most distal ileum, cecum, and ascending colon and mesenteric nonattachment were discovered. The last resulted in torsion around the superior mesenteric artery and secondary gan-
Received August 16, 1991; accepted November 12, 1991. Address reprint requests to Richard M. Pauli, M.D., Ph.D., Clinical Genetics Center, Room 353, 1500 Highland Avenue, Madison. WI 53705.
346
W.L. ROBERTSON ET AL.
Fig. 1. Age 7Yz years. Note bilateral decreased mass of shoulder girdle, pectoral, and proximal arm musculature.
grenous destruction of virtually all of the remaining ileum. Resection resulted in short gut syndrome, successfully treated with long-term central hyperalimentation. Eventually most of the symptoms associated with short gut syndrome resolved. A right, periumbilical gastroschisis, 4 cm in diameter resulted in extrusion of the stomach and all of the small bowel. The gastroschisis was repaired a t the time of intestinal resection. No contralateral abdominal wall defect (Reid et al., '86) was present. Bilateral decreased size and weakness of the upper limbs, shoulder girdle, and chest wall were noted in the newborn period. Electromyography in the arms failed to demonstrate any specific myopathic or neuropathic process. Examination at age 7% years showed the following: the biceps muscles were markedly decreased in mass bilaterally, as were the deltoids, while the triceps showed less severe hypoplasia; shoulder girdle musculature was hypoplastic with the left side slightly more severely affected than the right; pectoral muscles and the anterior axillary folds were also asymmetrically hypoplastic with the left side slightly less severely affected (Fig. 1).
Abnormalities of facial expression and a glabellar hemangioma were recognized a t birth. By clinical examination and electromyography with nerve conduction studies severe paresis of both the upper and lower distribution of the left VIIth cranial nerve could be demonstrated, including ipsilateral virtual absence of facial expression and marked limitation of voluntary movement of periorbital and perioral muscles. When examined a t 7% years of age these findings were still present: there was obvious facial asymmetry associated with markedly decreased resting tone of the muscles on the left (muscle mass seemed symmetric) without involvement of the muscles of mastication (Fig. 2A). In addition, examination showed absence of lateral rectus function bilaterally (Fig. 2B,C) indicative of bilateral VIth nerve paresis (left greater than right) as well as possible partial left IIIrd paresis suggested by poor inward gaze of the left eye (Fig. 2C). Tongue was normal in bulk, movement, and symmetry, and palatal elevation and gag reflex were normal. There were no facial anomalies other than those explicable on the basis of cranial nerve dysfunction. Limitation of arm and hand movement was recognized a t birth, including elbows fixed in extension, wrists fixed in flexion, ulnar deviation of the hands, and flexional camptodactyly of the fingers. Examination at age 7% years showed anterior sloping of the shoulders, prominent superficial venous patterning over the anterior trunk (Fig. 11, moderate limitation of shoulder mobility including elevation only to neutral bilaterally, and limited elbow flexion (5"-90" on the right and 10"-110"on the left) with limited supination on the left. Wrists were limited in dorsiflexion (90"-0" on the right and 100"-10" on the left). Hands showed camptodactylic contractures (Fig. 3) as follows. On the right the fifth finger had moderate limitation of metacarpal phalangeal joint (MCP) movement, marked limitation of proximal interphalangeal joint (PIP) movement, and flexion contracture of the distal interphalangeal joint (DIP); the fourth finger had an MCP which was fixed in extension, a PIP which showed 30" of flexion only, and a DIP which was also fixed in extension; the third finger had near normal MCP movement, severe f lexional camptodactyly with a tissue web of the PIP, and normal DIP movement; the second finger
VASCULAR ORIGIN OF ARTHROGRYPOSIS
347
Fig. 2. Age 7Yz years (A) Weakness of facial muscles on left with asymmetric nasolabial folds is evident. (B,C) Patient attempts forced lateral gaze to the left and right, respectively, showing bilateral VIth nerve paralysis and probable left IIIrd nerve paresis.
Fig. 3. Age 7% years. Arthrogrypotic hand abnormalities.
had a normal MCP, a fixed PIP, and a virtually normal DIP; the thumb was adducted and stiff but showed reasonably good opposition. On the left the fifth finger had good MCP mobility, mild limitation of PIP movement, and a DIP held completely flexed and immobile; the fourth finger had the MCP
and PIP fixed in extension, and moderate limitation of DIP mobility; the third finger had near normal MCP movement, a PIP fixed in extension, and normal DIP movement; the second finger was normal except that the PIP was fixed in extension; the thumb was normal.
348
W.L.ROBERTSON ET AL. ~~
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Poland Sequence
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Fig. 4. Summary of reports of associations among arthrogryposis multiplex congenita (AMC), intestinal atresia, gastroschisis, Mobius anomaly, and Poland sequence (including isolated pectoral hypoplasia). Nine of the 26 possible combinations have now been described.
The large filled circles indicate three or more reported cases, small filled circles are used where there have been only one or two reported instances, and open circles are for associations which have not yet been described.
Legs were uninvolved except for mild bilateral calcaneovalgus deformity of both feet in infancy. By age 7?f!z years legs and feet were normal except that the left foot was 1 cm longer than the right and that the toes were irregular in placement with mild overlap bilaterally. Other findings at 7% years of age included bilateral dimples over the acromion processes, mild lumbar lordosis, and diffuse hirsutism of the lower lumbar and sacral
region. Height was 104.4 cm (< 3rd %ile) and weight 17.2 kg (3rd %ile). She was mildly brachycephalic and had a head circumference of 49.3 cm (10th %ile). Intellectual development has been normal. Normal evaluations, in addition to those already mentioned, included echocardiography, computerized tomography of the calvarium, brainstem auditory evoked response testing, and electroencephalograPhY*
VASCULAR ORIGIN OF ARTHROGRYPOSIS DISCUSSION
Each of the five major characteristics present in this patient is typical in comparison to previous descriptions of their occurrence in isolation with the exception of the Poland sequence-like chest wall hypoplasia. There is nothing distinctive about the nonduodenal intestinal polyatresias with associated abnormalities of the mesentery when compared with instances in which this defect is unassociated with additional birth defects (Louw and Barnard, '55). Typical right sided gastroschisis not involving the umbilicus (Hoyme et al., '81) was present. As seen here, gastroschisis is most often right sided, probably because of asymmetric embryological vascular development in the abdominal wall (Hoyme et al., ,811. Mobius anomaly most often includes abnormality of lateral gaze (VIth nerve paresis) frequently with additional cranial pareses, most often of the VIIth cranial nerve (Van Allen and Blodi, '60) as was seen in this patient. The descriptive and nonspecific diagnosis of AMC was apparent a t birth. Subsequent assessment showed a constellation of contractures and posture consistent with the more specific diagnosis of amyoplasia (Hall et al., '83). Unilateral or asymmetric hypoplasia of the pectoral muscles may represent one end of a continuous spectrum of Poland sequence (Sujansky et al., '77; McGillivray and Lowry, '77). The complete Poland sequence consists of unilateral absence of the sternocostal head of the pectoralis major in association with syndactyly or symbrachydactyly (Poland, 1841). This patient is atypical even for Poland sequence variant because she has nearly symmetric bilateral involvement and more generalized muscular hypoplasia. However, all muscles which appear to be principally involved are supplied by the subclavian, axillary, and brachial arteries. Evidence suggests that each of the abnormalities present in this child, when found in isolation, has a vascular disruptive basis. Nonduodenal intestinal atresias and abnormalities of the mesentery have a well documented and experimentally demonstrated basis of vascular disruption. Louw and Barnard ('55) provided two kinds of evidence: autopsy findings from three patients with intestinal atresias showed associated absence of the inferior mesenteric arteries; ligation of the mesenteric arteries in fetal
349
puppies predictably resulted in intestinal atresias and abnormalities of the mesentery. Hoyme et al. ('81) have suggested that intrauterine interruption of the omphalomesenteric artery can lead to gastroschisis, an argument based both upon the recognized vascular pathogenesis of associated defects and on embryological development of the vasculature of the abdominal wall. The proximal portion of the right omphalomesenteric artery gives rise to the superior mesenteric artery. Their developmental interrelatedness has led to the hypothesis that abnormalities of the proximal portion of the right omphalomesenteric artery may lead to coexisting intestinal atresias in association with gastroschisis (Hoyme et al., '81). There is also evidence to suggest a vascular pathogenesis for the Poland sequence. Rheographic studies of the vasculature of eight patients showed decreased blood flow velocity on the affected side (Bouvet et al., '78) and Doppler scanning showed decreased diameter of the subclavian artery on the affected side (Merlob et al., '89). Bavinck and Weaver ('86) presented a coherent model of subclavian artery supply disruption as the basis for Poland sequence. Evidence in support of a vascular disruptive pathogenesis for Mobius anomaly is not so compelling. Indeed, there is considerable debate over the site of the primary lesion-whether it is the cranial nerve nuclei within the brainstem, the cranial nerves outside of the brainstem, or the extraocular muscles which are primarily affected (Pitner et al., '65).Several case reports suggest a primary lesion within the cranial nerve nuclei (Henderson, '39; Thakkar et al., '77). More recently Govaert et al. ('89) and Kuhn et al. ('90) showed by neuroimaging of patients with Mobius anomaly that there were cranial nerve nuclei abnormalities including calcifications. Such calcification may be most consistent with a prenatal ischemic event (Govaert et al., '89). A model for prenatal disruption of the vertebral arteries and/or basilar artery resulting in Mobius anomaly has been suggested (Bavinck and Weaver, '86). In addition, Lipson et al. ('89) found some evidence for vascular causes of Mobius anomaly in 15 human cases. There is less direct support of a vascular pathogenesis for AMC. Horoupian and Yoon ('80) described three instances of AMC in which anterior horn cell loss and ferrugination of some remaining neurons was found, indicat-
350
W.L. ROBERTSON ET AL
ing that neuronal destruction was most likely due to an ischemic event. Reid et a1 ('86) suggested that fetal and/or maternal vascular compromise during a critical period in the development of anterior horn cells may result in AMC, conceivably secondary to disruption of anterior spinal arteries (Lazorthes et al., '71). Associations of various combinations of the abnormalities seen in this child have been described (Fig. 4). Each of these coassociations independently supports the idea that all of the associated processes have a single pathogenetic basis-that is, vascular disruption. Reported dyad associations include gastroschisis and intestinal atresias (Hoyme et al., %l), Mobius anomaly and Poland sequence (Maino and Scharre, '89; Richards, '53), AMC and Mobius anomaly (Goldie, '85;Hanissian et al., '70; Sudarshan and Henderson, '391, AMC and Poland sequence (Sprofkin and Hillman, '561, AMC and intestinal atresia (Ilyina, '88; Reid et al., '86; Collins et al., '86), and AMC and gastroschisis (Reid et al., '86; Hall, Reed and Driscoll, '83). Two instances of triad combinations were found: AMC, intestinal atresias, and gastroschisis (Reid et al., '86>, and AMC, Mobius anomaly, and pectoral hypoplasia (Sprofkin and Hillman, '56). For the five characteristics seen in the patient reported here, by binomial expansion ( n= 5 , r 2 2 ) 26 such associations would be expected, of which, including this report, a t least eight have thus far been recognized. It is unlikely that any of these dyad and triad associations arose coincidentally. It is even less likely that the combination of all five abnormalities seen in this child would arise by chance. Rather, cooccurrence of arthrogryposis with four other apparently vascular-based abnormalities further supports the notion that arthrogryposis may have a vascular disruptive basis. In addition to those already discussed, other disorders for which a primary vascular disruptive event has been postulated include aplasia cutis congenita (Jaeggli et al., 'go), hemifacial microsomia (Poswillo, '731, porencephaly and other structural brain anomalies (Schinzel et al., '79), septooptic dysplasia (Mosier et al., '78), Klippel-Feil anomaly (Brill et al., '87), other vertebral anomalies (Bavinck and Weaver, '861, Sprengel deformity (Bavinck and Weaver, '86), terminal transverse limb defects (Hoyme et al., '82), radial ray anomalies
(Van Allen et al., '821, sirenomelia (Stevenson et al., '86), clubfoot (Hootnick et al., '82), twin-twin artery-artery disruptions (Benirschke and Harper, '771, and early amnionflimb-body wall disruptions (Luebke et al., '90). For 18 such vascularassociated birth defects (those listed above plus those present in the patient described-a conservative set of those disorders in which there is a t least some evidence for a vascular pathogenesis) a total of 310,745 different cooccurrences would be anticipated ( n= 18, 7-22), leaving about 310,700 still to be clinically identified! In the patient reported here, a vascular disruptive pathogenesis for all five characteristics would require disruption of the superior mesenteric artery, omphalomesenteric artery, vertebral and/or basilar arteries, subclavian arteries, and anterior spinal arteries. Based on the embryological development of these vessels we suggest that either a simultaneous disruption or a cluster of disruptive events occurred at around 6 to 8 weeks postconception (Hamilton et al., '72).What primary event resulted in such diffuse vascular or hypoxic effects is undetermined. LITERATURE CITED Bavinck, J.N.B., and D.D. Weaver (1986) Subclavian artery supply disruption sequence: Hypothesis of a vascular etiologyfor Poland, Klippel-Feil,and Mobius anomalies. Am. J. Med. Genet., 23:903-918. Benirschke, K., and V.D.R. Harper (1977) The acardiac anomaly. Teratology, 15:311-316. Bouvet, J.-P., D. Leveque, F. Bernetieres, and J . J . Gros (1978) Vascular origin of Poland syndrome? A comparative rheographic study of the vascularisation of the arms in eight patients. Eur. J. Pediatr., 128:1726. Brill, C.B., R.G. Peyster, M.S. Keller, and L. Galtman (1987) Isolation of the right subclavian artery with subclavian steal in a child with Klippel-Feil anomaly: An example of the subclavian artery supply disruption sequence. Am. J. Med. Genet., 26:933-940. Collins, D.L., K. Kimura, A. Morgan, D.G. Johnson, C. Leonard, and M.C. Jones (1986) Multiple intestinal atresia and amyoplasia congenita in four unrelated infants: A new association.J. Pediatr. Surg., 21 :331333. Govaert, P., P. Vanhaesebrouck, C. De F'raeter, U. Frankel, and J . Leroy (1989) Moebius sequence and prenatal brainstem ischemia. Pediatrics, 84570-573. Hall, J.G., S.D. Reed, and E.P. Driscoll (1983) Part I. Amyoplasia: A common, sporadic condition with congenital contractures. Am. J. Med. Genet., 15:571-590. Hamilton, W.J., J.D. Boyd, and H.W. Mossman (1972) Human Embryology,4th ed. Williams & Wilkins, Baltimore. Hanissian, A.S., F. Fuste, W.T. Hayes, and J.M. Duncan (1970) Mobius syndrome in twins. Am. J . Dis. Child., 120:472-475.
VASCULAR ORIGIN OF ARTHROGRYPOSIS Henderson, J.L. (1939) The congenital facial diplegia features, pathology and etiology. Hootnick, D.R., E.M. Levinsohn, R.J. Crider, and D.S. Packard (1982) Congenital arterial malformations associated with clubfoot A report of two cases. Clin. Orthop., 167: 160-163. Horoupian D.S., and J.J. Yoon (1988) Neuropathic arthrogryposis multiplex congenita and intrauterine ischemia of anterior horn cells: a hypothesis. Clin. Neuropathol., 7:285-293. Hoyme, H.E., M.C. Higginbottom, and K.L. Jones (1981) The vascular pathogenesis of gastroschisis: Intrauterine interruption of the omphalomesentericartery. J. Pediatr., 98:228-231. Hoyme, H.E., K.L. Jones, M.I. Van Allen, B.S. Saunders, and K. Benirschke (1982) Vascular pathogenesis of transverse limb reduction defects. J. Pediatr., 101:839-843. Ilyina, H.G. (1988) Intestinal atresia and arthrogryposis. Am. J. Med. Genet., 29:673-674. Jaeggi, E., C. Kind, and R. Morger (1990) Congenital scalp and skull defects with terminal transverse limb anomalies (Adams-Oliver syndrome): Report of three additional cases. Eur. J. Pediatr., 149~565-566. Kuhn, M.J., H.B. Clark, A. Morales, and P.C. Shekar (1990) Group 111 Mobius syndrome: CT and MR findings. Am. J. Neuroradiol., 11:903-904. Lazorthes, G., A. Gouaze, J.O. Zadeh, J.J. Santini, Y. Lazorthes, and P. Burdin (1971) Arterial vascularization of the spinal cord Recent studies of the anastomotic substitution pathways. J . Neurosurg., 35:253262. Lipson, A.H., W.S. Webster, P.D.C. Brown-Woodman, and R.A. Osborn (1989) Moebius syndrome: Animal model-human correlations and evidence for a brainstem vascular etiology. Teratology, 40:339-350. Louw, J.H., and C.N. Barnard (1955) Congenital intestinal atresia: Observations on its origin. Lancet, 2: 1065-1067. Luebke, H.J., C.A. Reiser, and R.M. Pauli (1990) Fetal disruptions: Assessment of frequency, heterogeneity, and embryologic mechanisms in a population referred to a community-based stillbirth assessment program. Am. J. Med. Genet., 36:56-72. Maino, D.M., and J.E. Scharre (1989) Poland-Mobius syndrome: A case report. Opt. Vision Sci., 66:621-625. McGillivray, B.C., and R.B. Lowry (1977) Poland syndrome in British Columbia: Incidence and reproductive experience of affected persons. Am. J . Med. Genet., 1:65-74. Merlob, P., A. Schonfeld, Y. Ovadia, and S.H. Reisner
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(1989) Real-time echo-doppler duplex scanner in the evaluation of patients with Poland sequence. Eur. J . Obstet. Gynecol. Reprod. Biol., 32:103-108. Mosier, M.A., M.F. Lieberman, W.R. Green, and D.L. Knox (1978) Hypoplasia of the optic nerve. Arch. Ophthalmol., 96~1437-1442. Pitner, S.E., J.E. Edwards, and W.F. McCormick (1965) Observations on the pathology of Moebius syndrome. J . Neurol. Neurosurg. Psychiat., 28:362-374. Poland, A. (1841) Deficiency of the pectoral muscles. Guy Hosp. Report, 6:191-192. Poswillo, D. (1973) The pathogenesis of the first and second branchial arch syndrome. Oral Surg. Oral Med. Oral Pathol., 35:302-328. Reid, C.O.M.V., J.G. Hall, C. Anderson, M. Bocian, J . Carey, T. Costa, C. Curry, F. Greenberg, E.W. Horton, M. Jones, C. Lafer, E. Larson, M. Lubinsky, B. McGillivray, M. Pembry, J. Popkin, M. Seller, V. Siebert, and A. Verhagen (1986) Association of amyoplasia with gastroschisis, bowel atresia, and defects of the muscular layer of the trunk. Am. J . Med. Genet., 24:701-710. Richards, R.N. (1953) The Mobius syndrome. J . Bone Joint Surg. (A), 35:437-444. Schinzel, A.A.G.L., D.W. Smith, and J.R. Miller (1979) Monozygotic twinning and structural defects. J . Pediatr., 95:921-930. Sprofkin, B.E., and J.W. Hillman (1956) Moebius's syndrome-congenital oculofacial paralysis. Neurology, 6:50-54. Stevenson, R.E., K.L. Jones, M.C. Phelan, M.C. Jones, M. Barr, C. Clericuzio, R.A. Harley, and K. Benirschke (1986) Vascular steal: The pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics, 78:451-457. Sudarshan, A. and W.D. Goldie (1985) The spectrum of congenital facial diplegia (Moebius syndrome). Pediatr. Neurol., 1:180-184. Sujansky, E., V.M. Riccardi, and A.L. Matthew (1977) The familial occurrence of Poland syndrome. Birth Defects, I3(3A):117-121. Thakkar, N., W. ONeill, J . Duvally, C. Liu, and M. Ambler (1977) Mobius syndrome due to brain stem tegmental necrosis. Arch. Neurol., 34:124-126. Van Allen, M.I., H.E. Hoyme, and K.L. Jones (1982) Vascular pathogenesis of limb defects. I. Radial artery anatomy in radial aplasia. J . Pediatr., 101:832-838. Van Allen, M.W., and F.C. Blodi (1960) Neurologic aspects of the Mobius syndrome: A case study with electromyography of the extraocular and facial muscles. Neurology, 10:249-259.
